Biology subjects

Perez-Fernandez, J.

Publications and source records attributed to Perez-Fernandez, J..

5 recordsLinked to original sources

bioRxiv2026

MYC overexpression drives poor prognosis and differential sensitivity to treatments according to TP53 status in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a lymphoid neoplasm with very heterogeneous clinical and biological behavior. Among molecular variables, TP53 alterations are well-established adverse prognostic markers; however, MYC activation, which has been linked to disease progression, has not been completely defined in terms of clinical and biological impact, particularly in relation to TP53 status. Here, we investigated the effects of MYC overexpression according to TP53 status using clinical and transcriptomic data from CLL patients and novel cellular models. CLL patients with TP53WT and MYC overexpression exhibited significantly shorter time to first treatment and overall survival, indicating an aggressive disease course comparable to that of patients with TP53 alterations. Consistently, MYC overexpression in in vitro TP53WTmodels was associated with increased proliferation, enrichment of AKT/mTOR signaling and upregulation of genes involved in leukemogenesis and tumor progression such as FOXO6. Moreover, MYC overexpression was associated with increased sensitivity to venetoclax in TP53WT cells. By contrast, the concurrence of MYC overexpression and TP53 dysfunction conferred resistance to conventional CLL therapies such as BCL2 or BTK inhibitors. Of note, we identified a glycolysis inhibitor, in monotherapy or combined with BKT inhibitors, as a potential therapeutic strategy for CLL patients harboring MYC overexpression and TP53 alterations.

cancer biology↗

bioRxiv2026

Brain inputs to the vestibular nuclei in lampreys

To avoid image blurring, the vestibulo-ocular (VOR) and the optokinetic (OKR) reflexes stabilize gaze. In all vertebrates, the VOR is mediated via direct projections from the vestibular nuclei to the motor nuclei that control the extraocular muscles. Lampreys show three vestibular nuclei that are well characterized in terms of their projections and sensory inputs, but much less is known about their inputs from other brain regions and the connectivity between them. Using tracer injections and electrophysiological recordings, we show that the lamprey vestibular nuclei are largely interconnected, while their inputs from other brain regions are scarce. The main rostral areas projecting to the vestibular nuclei are the pretectum and the ventral tier of the thalamus, which send ipsilateral inputs to the three vestibular nuclei.

neuroscience↗

bioRxiv2024

Direct retino-iridal projections and intrinsic iris contraction mediate the pupillary light reflex in early vertebrates

The pupillary light reflex (PLR) adapts the amount of light reaching the retina, protecting it and improving image formation. Two PLR mechanisms have been described in vertebrates. First, the pretectum receives retinal inputs and projects to the Edinger-Westphal nucleus (EWN), which targets the ciliary ganglion through the oculomotor nerve (nIII). Postganglionic fibers enter the eye-globe, travelling to the iris sphincter muscle. Additionally, some vertebrates exhibit an iris-intrinsic PLR mechanism mediated by sphincter muscle cells that express melanopsin inducing muscle contraction. Given the high degree of conservation of the lamprey visual system, we investigated the mechanisms underlying the PLR to shed light onto their evolutionary origins. Recently, a PLR mediated by melanopsin was demonstrated in lampreys, suggested to be brain mediated. Remarkably, we found that PLR is instead mediated by direct retino-iridal cholinergic projections, a mechanism not demonstrated before, although suggested to be present in mice. This retina-mediated PLR acts synergistically with the iris-intrinsic mechanism mediated by melanopsin, which has contribution of gap junctions, as in other vertebrates. In contrast, we show that lampreys lack the brain-mediated PLR. Our results suggest that two eye-intrinsic PLR mechanisms were present in early vertebrate evolution, whereas the brain-mediated PLR has a more recent origin.

neuroscience↗

bioRxiv2023

Functional development of eye movements and visuomotor circuits in lampreys

Animals constantly redirect their gaze away or towards relevant targets and, besides these goal-oriented responses, stabilizing movements clamp the visual scene avoiding image blurring. The vestibulo-ocular (VOR) and the optokinetic reflexes are the main contributors to gaze stabilization, whereas the optic tectum integrates multisensory information and generates orienting/evasive gaze movements in all vertebrates. Lampreys show a unique stepwise development of the visual system whose understanding provides important insights into the evolution and development of vertebrate vision. Although the developmental emergence of the visual components, and the retinofugal pathways have been described, the functional development of the visual system and the development of the downstream pathways controlling gaze are still unknown. Here, we show that VOR followed by light-evoked eye movements are the first to appear already in larvae, despite their burrowed lifestyle. However, the circuits controlling goal-oriented responses emerge later, in larvae in nonparasitic lampreys but during late metamorphosis in parasitic lampreys. The appearance of stabilizing responses earlier than goal-oriented likely reflects their evolution, and its stepwise emergence offers a unique opportunity to isolate the functioning of their underlying circuits.

neuroscience↗

bioRxiv2021

Visuo-vestibular gaze control - conserved subcortical processing

Gaze stabilization compensates for movements of the head or external environment to minimize image blurring, which is critical for visually-guided behaviors. Multisensory information is used to stabilize the visual scene on the retina via the vestibulo-ocular (VOR) and optokinetic (OKR) reflexes. While the organization of neuronal circuits underlying VOR is well described across vertebrates, less is known about the contribution and evolutionary origin of the OKR circuits. Moreover, the integration of these two sensory modalities is still poorly understood. Here, we developed a novel experimental model, the isolated lamprey eye-brain-labyrinth preparation, to analyze the neuronal pathways underlying visuo-vestibular integration which allowed electrophysiological recordings while applying vestibular stimulation using a moving platform, coordinated with visual stimulation via two screens. We show that lampreys exhibit robust visuo-vestibular integration, with optokinetic information processed in the pretectum and integrated with vestibular inputs at several subcortical levels. The enhanced eye movement response to multimodal stimulation favored the vestibular response at increased velocities. The optokinetic signals can be downregulated from tectum. Additionally, saccades are present in the form of nystagmus. The lamprey represents the oldest living group of vertebrates, thus all basic components of the visuo-vestibular control of gaze were present already at the dawn of vertebrate evolution.

neuroscience↗